- •CONTENTS
- •Preface
- •Contributors
- •1 Introduction to Toxicology
- •1.1 Definition and Scope, Relationship to Other Sciences, and History
- •1.1.2 Relationship to Other Sciences
- •1.1.3 A Brief History of Toxicology
- •1.3 Sources of Toxic Compounds
- •1.3.1 Exposure Classes
- •1.3.2 Use Classes
- •1.4 Movement of Toxicants in the Environment
- •Suggested Reading
- •2.1 Introduction
- •2.2 Cell Culture Techniques
- •2.2.1 Suspension Cell Culture
- •2.2.2 Monolayer Cell Culture
- •2.2.3 Indicators of Toxicity in Cultured Cells
- •2.3 Molecular Techniques
- •2.3.1 Molecular Cloning
- •2.3.2 cDNA and Genomic Libraries
- •2.3.3 Northern and Southern Blot Analyses
- •2.3.4 Polymerase Chain Reaction (PCR)
- •2.3.5 Evaluation of Gene Expression, Regulation, and Function
- •2.4 Immunochemical Techniques
- •Suggested Reading
- •3.1 Introduction
- •3.2 General Policies Related to Analytical Laboratories
- •3.2.1 Standard Operating Procedures (SOPs)
- •3.2.2 QA/QC Manuals
- •3.2.3 Procedural Manuals
- •3.2.4 Analytical Methods Files
- •3.2.5 Laboratory Information Management System (LIMS)
- •3.3 Analytical Measurement System
- •3.3.1 Analytical Instrument Calibration
- •3.3.2 Quantitation Approaches and Techniques
- •3.4 Quality Assurance (QA) Procedures
- •3.5 Quality Control (QC) Procedures
- •3.6 Summary
- •Suggested Reading
- •4 Exposure Classes, Toxicants in Air, Water, Soil, Domestic and Occupational Settings
- •4.1 Air Pollutants
- •4.1.1 History
- •4.1.2 Types of Air Pollutants
- •4.1.3 Sources of Air Pollutants
- •4.1.4 Examples of Air Pollutants
- •4.1.5 Environmental Effects
- •4.2 Water and Soil Pollutants
- •4.2.1 Sources of Water and Soil Pollutants
- •4.2.2 Examples of Pollutants
- •4.3 Occupational Toxicants
- •4.3.1 Regulation of Exposure Levels
- •4.3.2 Routes of Exposure
- •4.3.3 Examples of Industrial Toxicants
- •Suggested Reading
- •5 Classes of Toxicants: Use Classes
- •5.1 Introduction
- •5.2 Metals
- •5.2.1 History
- •5.2.2 Common Toxic Mechanisms and Sites of Action
- •5.2.3 Lead
- •5.2.4 Mercury
- •5.2.5 Cadmium
- •5.2.6 Chromium
- •5.2.7 Arsenic
- •5.2.8 Treatment of Metal Poisoning
- •5.3 Agricultural Chemicals (Pesticides)
- •5.3.1 Introduction
- •5.3.3 Organochlorine Insecticides
- •5.3.4 Organophosphorus Insecticides
- •5.3.5 Carbamate Insecticides
- •5.3.6 Botanical Insecticides
- •5.3.7 Pyrethroid Insecticides
- •5.3.8 New Insecticide Classes
- •5.3.9 Herbicides
- •5.3.10 Fungicides
- •5.3.11 Rodenticides
- •5.3.12 Fumigants
- •5.3.13 Conclusions
- •5.4 Food Additives and Contaminants
- •5.5 Toxins
- •5.5.1 History
- •5.5.2 Microbial Toxins
- •5.5.3 Mycotoxins
- •5.5.4 Algal Toxins
- •5.5.5 Plant Toxins
- •5.5.6 Animal Toxins
- •5.6 Solvents
- •5.7 Therapeutic Drugs
- •5.8 Drugs of Abuse
- •5.9 Combustion Products
- •5.10 Cosmetics
- •Suggested Reading
- •6 Absorption and Distribution of Toxicants
- •6.1 Introduction
- •6.2 Cell Membranes
- •6.3 Mechanisms of Transport
- •6.3.1 Passive Diffusion
- •6.4 Physicochemical Properties Relevant to Diffusion
- •6.4.1 Ionization
- •6.5 Routes of Absorption
- •6.5.1 Extent of Absorption
- •6.5.2 Gastrointestinal Absorption
- •6.5.3 Dermal Absorption
- •6.5.4 Respiratory Penetration
- •6.6 Toxicant Distribution
- •6.6.1 Physicochemical Properties and Protein Binding
- •6.7 Toxicokinetics
- •Suggested Reading
- •7 Metabolism of Toxicants
- •7.1 Introduction
- •7.2 Phase I Reactions
- •7.2.4 Nonmicrosomal Oxidations
- •7.2.5 Cooxidation by Cyclooxygenases
- •7.2.6 Reduction Reactions
- •7.2.7 Hydrolysis
- •7.2.8 Epoxide Hydration
- •7.2.9 DDT Dehydrochlorinase
- •7.3 Phase II Reactions
- •7.3.1 Glucuronide Conjugation
- •7.3.2 Glucoside Conjugation
- •7.3.3 Sulfate Conjugation
- •7.3.4 Methyltransferases
- •7.3.7 Acylation
- •7.3.8 Phosphate Conjugation
- •Suggested Reading
- •8 Reactive Metabolites
- •8.1 Introduction
- •8.2 Activation Enzymes
- •8.3 Nature and Stability of Reactive Metabolites
- •8.4 Fate of Reactive Metabolites
- •8.4.1 Binding to Cellular Macromolecules
- •8.4.2 Lipid Peroxidation
- •8.4.3 Trapping and Removal: Role of Glutathione
- •8.5 Factors Affecting Toxicity of Reactive Metabolites
- •8.5.1 Levels of Activating Enzymes
- •8.5.2 Levels of Conjugating Enzymes
- •8.5.3 Levels of Cofactors or Conjugating Chemicals
- •8.6 Examples of Activating Reactions
- •8.6.1 Parathion
- •8.6.2 Vinyl Chloride
- •8.6.3 Methanol
- •8.6.5 Carbon Tetrachloride
- •8.6.8 Acetaminophen
- •8.6.9 Cycasin
- •8.7 Future Developments
- •Suggested Reading
- •9.1 Introduction
- •9.2 Nutritional Effects
- •9.2.1 Protein
- •9.2.2 Carbohydrates
- •9.2.3 Lipids
- •9.2.4 Micronutrients
- •9.2.5 Starvation and Dehydration
- •9.2.6 Nutritional Requirements in Xenobiotic Metabolism
- •9.3 Physiological Effects
- •9.3.1 Development
- •9.3.2 Gender Differences
- •9.3.3 Hormones
- •9.3.4 Pregnancy
- •9.3.5 Disease
- •9.3.6 Diurnal Rhythms
- •9.4 Comparative and Genetic Effects
- •9.4.1 Variations Among Taxonomic Groups
- •9.4.2 Selectivity
- •9.4.3 Genetic Differences
- •9.5 Chemical Effects
- •9.5.1 Inhibition
- •9.5.2 Induction
- •9.5.3 Biphasic Effects: Inhibition and Induction
- •9.6 Environmental Effects
- •9.7 General Summary and Conclusions
- •Suggested Reading
- •10 Elimination of Toxicants
- •10.1 Introduction
- •10.2 Transport
- •10.3 Renal Elimination
- •10.4 Hepatic Elimination
- •10.4.2 Active Transporters of the Bile Canaliculus
- •10.5 Respiratory Elimination
- •10.6 Conclusion
- •Suggested Reading
- •11 Acute Toxicity
- •11.1 Introduction
- •11.2 Acute Exposure and Effect
- •11.3 Dose-response Relationships
- •11.4 Nonconventional Dose-response Relationships
- •11.5 Mechanisms of Acute Toxicity
- •11.5.1 Narcosis
- •11.5.2 Acetylcholinesterase Inhibition
- •11.5.3 Ion Channel Modulators
- •11.5.4 Inhibitors of Cellular Respiration
- •Suggested Reading
- •12 Chemical Carcinogenesis
- •12.1 General Aspects of Cancer
- •12.2 Human Cancer
- •12.2.1 Causes, Incidence, and Mortality Rates of Human Cancer
- •12.2.2 Known Human Carcinogens
- •12.3 Classes of Agents Associated with Carcinogenesis
- •12.3.2 Epigenetic Agents
- •12.4 General Aspects of Chemical Carcinogenesis
- •12.5 Initiation-Promotion Model for Chemical Carcinogenesis
- •12.6 Metabolic Activation of Chemical Carcinogens and DNA Adduct Formation
- •12.7 Oncogenes
- •12.8 Tumor Suppressor Genes
- •12.8.1 Inactivation of Tumor Suppressor Genes
- •12.8.2 p53 Tumor Suppressor Gene
- •12.9 General Aspects of Mutagenicity
- •12.10 Usefulness and Limitations of Mutagenicity Assays for the Identification of Carcinogens
- •Suggested Reading
- •13 Teratogenesis
- •13.1 Introduction
- •13.2 Principles of Teratology
- •13.3 Mammalian Embryology Overview
- •13.4 Critical Periods
- •13.5 Historical Teratogens
- •13.5.1 Thalidomide
- •13.5.2 Accutane (Isotetrinoin)
- •13.5.3 Diethylstilbestrol (DES)
- •13.5.4 Alcohol
- •13.6 Testing Protocols
- •13.6.1 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use
- •13.6.3 Alternative Test Methods
- •13.7 Conclusions
- •Suggested Reading
- •14 Hepatotoxicity
- •14.1 Introduction
- •14.1.1 Liver Structure
- •14.1.2 Liver Function
- •14.2 Susceptibility of the Liver
- •14.3 Types of Liver Injury
- •14.3.1 Fatty Liver
- •14.3.2 Necrosis
- •14.3.3 Apoptosis
- •14.3.4 Cholestasis
- •14.3.5 Cirrhosis
- •14.3.6 Hepatitis
- •14.3.7 Oxidative Stress
- •14.3.8 Carcinogenesis
- •14.4 Mechanisms of Hepatotoxicity
- •14.5 Examples of Hepatotoxicants
- •14.5.1 Carbon Tetrachloride
- •14.5.2 Ethanol
- •14.5.3 Bromobenzene
- •14.5.4 Acetaminophen
- •14.6 Metabolic Activation of Hepatotoxicants
- •Suggested Reading
- •15 Nephrotoxicity
- •15.1 Introduction
- •15.1.1 Structure of the Renal System
- •15.1.2 Function of the Renal System
- •15.2 Susceptibility of the Renal System
- •15.3 Examples of Nephrotoxicants
- •15.3.1 Metals
- •15.3.2 Aminoglycosides
- •15.3.3 Amphotericin B
- •15.3.4 Chloroform
- •15.3.5 Hexachlorobutadiene
- •Suggested Reading
- •16 Toxicology of the Nervous System
- •16.1 Introduction
- •16.2 The Nervous system
- •16.2.1 The Neuron
- •16.2.2 Neurotransmitters and their Receptors
- •16.2.3 Glial Cells
- •16.3 Toxicant Effects on the Nervous System
- •16.3.1 Structural Effects of Toxicants on Neurons
- •16.3.2 Effects of Toxicants on Other Cells
- •16.4 Neurotoxicity Testing
- •16.4.1 In vivo Tests of Human Exposure
- •16.4.2 In vivo Tests of Animal Exposure
- •16.4.3 In vitro Neurochemical and Histopathological End Points
- •16.5 Summary
- •Suggested Reading
- •17 Endocrine System
- •17.1 Introduction
- •17.2 Endocrine System
- •17.2.1 Nuclear Receptors
- •17.3 Endocrine Disruption
- •17.3.1 Hormone Receptor Agonists
- •17.3.2 Hormone Receptor Antagonists
- •17.3.3 Organizational versus Activational Effects of Endocrine Toxicants
- •17.3.4 Inhibitors of Hormone Synthesis
- •17.3.5 Inducers of Hormone Clearance
- •17.3.6 Hormone Displacement from Binding Proteins
- •17.4 Incidents of Endocrine Toxicity
- •17.4.1 Organizational Toxicity
- •17.4.2 Activational Toxicity
- •17.4.3 Hypothyroidism
- •17.5 Conclusion
- •Suggested Reading
- •18 Respiratory Toxicity
- •18.1 Introduction
- •18.1.1 Anatomy
- •18.1.2 Cell Types
- •18.1.3 Function
- •18.2 Susceptibility of the Respiratory System
- •18.2.1 Nasal
- •18.2.2 Lung
- •18.3 Types of Toxic Response
- •18.3.1 Irritation
- •18.3.2 Cell Necrosis
- •18.3.3 Fibrosis
- •18.3.4 Emphysema
- •18.3.5 Allergic Responses
- •18.3.6 Cancer
- •18.3.7 Mediators of Toxic Responses
- •18.4 Examples of Lung Toxicants Requiring Activation
- •18.4.1 Introduction
- •18.4.2 Monocrotaline
- •18.4.3 Ipomeanol
- •18.4.4 Paraquat
- •18.5 Defense Mechanisms
- •Suggested Reading
- •19 Immunotoxicity
- •19.1 Introduction
- •19.2 The Immune System
- •19.3 Immune Suppression
- •19.4 Classification of Immune-Mediated Injury (Hypersensitivity)
- •19.5 Effects of Chemicals on Allergic Disease
- •19.5.1 Allergic Contact Dermatitis
- •19.5.2 Respiratory Allergens
- •19.5.3 Adjuvants
- •19.6 Emerging Issues: Food Allergies, Autoimmunity, and the Developing Immune System
- •Suggested Reading
- •20 Reproductive System
- •20.1 Introduction
- •20.2 Male Reproductive Physiology
- •20.3 Mechanisms and Targets of Male Reproductive Toxicants
- •20.3.1 General Mechanisms
- •20.3.2 Effects on Germ Cells
- •20.3.3 Effects on Spermatogenesis and Sperm Quality
- •20.3.4 Effects on Sexual Behavior
- •20.3.5 Effects on Endocrine Function
- •20.4 Female Reproductive Physiology
- •20.5 Mechanisms and Targets of Female Reproductive Toxicants
- •20.5.1 Tranquilizers, Narcotics, and Social Drugs
- •20.5.2 Endocrine Disruptors (EDs)
- •20.5.3 Effects on Germ Cells
- •20.5.4 Effects on the Ovaries and Uterus
- •20.5.5 Effects on Sexual Behavior
- •Suggested Reading
- •21 Toxicity Testing
- •21.1 Introduction
- •21.2 Experimental Administration of Toxicants
- •21.2.1 Introduction
- •21.2.2 Routes of Administration
- •21.3 Chemical and Physical Properties
- •21.4 Exposure and Environmental Fate
- •21.5 In vivo Tests
- •21.5.1 Acute and Subchronic Toxicity Tests
- •21.5.2 Chronic Tests
- •21.5.3 Reproductive Toxicity and Teratogenicity
- •21.5.4 Special Tests
- •21.6 In vitro and Other Short-Term Tests
- •21.6.1 Introduction
- •21.6.2 Prokaryote Mutagenicity
- •21.6.3 Eukaryote Mutagenicity
- •21.6.4 DNA Damage and Repair
- •21.6.5 Chromosome Aberrations
- •21.6.6 Mammalian Cell Transformation
- •21.6.7 General Considerations and Testing Sequences
- •21.7 Ecological Effects
- •21.7.1 Laboratory Tests
- •21.7.2 Simulated Field Tests
- •21.7.3 Field Tests
- •21.8 Risk Analysis
- •21.9 The Future of Toxicity Testing
- •Suggested Reading
- •22 Forensic and Clinical Toxicology
- •22.1 Introduction
- •22.2 Foundations of Forensic Toxicology
- •22.3 Courtroom Testimony
- •22.4.1 Documentation Practices
- •22.4.2 Considerations for Forensic Toxicological Analysis
- •22.4.3 Drug Concentrations and Distribution
- •22.5 Laboratory Analyses
- •22.5.1 Colorimetric Screening Tests
- •22.5.2 Thermal Desorption
- •22.5.6 Enzymatic Immunoassay
- •22.6 Analytical Schemes for Toxicant Detection
- •22.7 Clinical Toxicology
- •22.7.1 History Taking
- •22.7.2 Basic Operating Rules in the Treatment of Toxicosis
- •22.7.3 Approaches to Selected Toxicoses
- •Suggested Reading
- •23 Prevention of Toxicity
- •23.1 Introduction
- •23.2 Legislation and Regulation
- •23.2.1 Federal Government
- •23.2.2 State Governments
- •23.2.3 Legislation and Regulation in Other Countries
- •23.3 Prevention in Different Environments
- •23.3.1 Home
- •23.3.2 Workplace
- •23.3.3 Pollution of Air, Water, and Land
- •23.4 Education
- •Suggested Reading
- •24 Human Health Risk Assessment
- •24.1 Introduction
- •24.2 Risk Assessment Methods
- •24.2.2 Exposure Assessment
- •24.2.3 Dose Response and Risk Characterization
- •24.3 Noncancer Risk Assessment
- •24.3.1 Default Uncertainty and Modifying Factors
- •24.3.2 Derivation of Developmental Toxicant RfD
- •24.3.3 Determination of RfD and RfC of Naphthalene with the NOAEL Approach
- •24.3.4 Benchmark Dose Approach
- •24.3.5 Determination of BMD and BMDL for ETU
- •24.3.6 Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient
- •24.3.7 Chemical Mixtures
- •24.4 Cancer Risk Assessment
- •24.5 PBPK Modeling
- •Suggested Reading
- •25 Analytical Methods in Toxicology
- •25.1 Introduction
- •25.2 Chemical and Physical Methods
- •25.2.1 Sampling
- •25.2.2 Experimental Studies
- •25.2.3 Forensic Studies
- •25.2.4 Sample Preparation
- •25.2.6 Spectroscopy
- •25.2.7 Other Analytical Methods
- •Suggested Reading
- •26 Basics of Environmental Toxicology
- •26.1 Introduction
- •26.2 Environmental Persistence
- •26.2.1 Abiotic Degradation
- •26.2.2 Biotic Degradation
- •26.2.3 Nondegradative Elimination Processes
- •26.3 Bioaccumulation
- •26.4 Toxicity
- •26.4.1 Acute Toxicity
- •26.4.2 Mechanisms of Acute Toxicity
- •26.4.3 Chronic Toxicity
- •26.4.5 Abiotic and Biotic Interactions
- •26.5 Conclusion
- •Suggested Reading
- •27.1 Introduction
- •27.2 Sources of Toxicants to the Environment
- •27.3 Transport Processes
- •27.3.1 Advection
- •27.3.2 Diffusion
- •27.4 Equilibrium Partitioning
- •27.5 Transformation Processes
- •27.5.1 Reversible Reactions
- •27.5.2 Irreversible Reactions
- •27.6 Environmental Fate Models
- •Suggested Reading
- •28 Environmental Risk Assessment
- •28.1 Introduction
- •28.2 Formulating the Problem
- •28.2.1 Selecting Assessment End Points
- •28.2.2 Developing Conceptual Models
- •28.2.3 Selecting Measures
- •28.3 Analyzing Exposure and Effects Information
- •28.3.1 Characterizing Exposure
- •28.3.2 Characterizing Ecological Effects
- •28.4 Characterizing Risk
- •28.4.1 Estimating Risk
- •28.4.2 Describing Risk
- •28.5 Managing Risk
- •Suggested Reading
- •29 Future Considerations for Environmental and Human Health
- •29.1 Introduction
- •29.2 Risk Management
- •29.3 Risk Assessment
- •29.4 Hazard and Exposure Assessment
- •29.5 In vivo Toxicity
- •29.6 In vitro Toxicity
- •29.7 Biochemical and Molecular Toxicology
- •29.8 Development of Selective Toxicants
- •Glossary
- •Index
NONCANCER RISK ASSESSMENT |
427 |
Response |
|
Range of |
Experimental |
Inference |
Observable Range |
Figure 24.2 Dose-response curve, with emphasis on the shape of the dose-response function below the experimentally observable range and therefore the range of inference where people are realistically exposed.
U-shaped effects can be explained in terms of homeostatic adjustments or overcorrections in the operation of feedback mechanisms. Examples of studies with data fitting a U-shaped curve include the hormetic effect of organic lead on body growth in rats (Cragg and Rees, 1984) and peripheral nerve conduction velocity in children at low doses (Ewert et al., 1986). Similar relationships have been observed with alcohol and nicotine in humans. It has been proposed that because thresholds are inherent in U-shaped dose-response curves, the linear no-threshold extrapolation method is not an appropriate approach for regulating hormetic agents. The current risk assessment paradigm used by US EPA and other federal agencies does not conflict with the concept of hormesis, but it has been proposed that the risk assessor’s analyzes make an active consideration of the data and the application of that data in the low dose portion of the dose-response curve for hormetic agents.
24.3NONCANCER RISK ASSESSMENT
The noncancer risk assessment process assumes a threshold. For many noncarcinogenic effects, protective mechanisms are believed to exist that must be overcome before an adverse effect is manifested. At the cellular level for some toxicant, a range of exposures exists from zero to some finite value that can be tolerated by the organism with essentially no chance of expression of adverse effects. The aim here in risk assessment is to identify the upper bound of this tolerance range (i.e., the maximum subthreshold level). This approach involves obtaining the no observed adverse effect level. NOAEL is the highest dose level that does not produce a significant elevated increase in an adverse response. Significance refers to biological and statistical criteria and is dependent on dose levels tested, number of animals, background incidence in the unexposed control groups. Sometimes there is insufficient data to arrive at a NOAEL, and a LOAEL (lowest observed adverse effect level) is derived. The NOAEL is the key datum obtained from the study of the dose-response relationship. The NOAEL is used to calculate reference doses (RfD) for chronic oral exposures and reference concentrations (RfC) for chronic inhalation exposures as per EPA. Other agencies, such as the ATSDR and WHO, use the NOAEL to calculate minimum risk levels (MRLs) and acceptable daily intakes (ADI). The US EPA describes the RfD as an estimate, with uncertainty spanning an order of magnitude, of a daily exposure to the human population, including
428 HUMAN HEALTH RISK ASSESSMENT
sensitive subgroups, that is likely to be without appreciable deleterious effects during a lifetime. In deriving reference doses, ADIs, or MRLs, the NOAEL is divided by uncertainty factors (UF) as per EPA (EPA, 1989) and ATSDR (ATSDR, 1993) and by modifying factors (MF) as per EPA:
RfD = |
NOAEL |
US EPA; |
||||
|
|
|
|
, |
||
(UF |
|
MF) |
||||
|
|
|
|
|
|
|
MRL = |
NOAEL |
ATSDR. |
||||
|
|
, |
|
|||
UF |
|
|
The calculated RfD or RfC is based on the selected critical study and selected critical end point. The risk assessor may obtain numerous studies where the toxicant may have more than one toxic end point, and thus there may be many NOAELs to choose from the literature. In some instances poor data quality may be used to exclude those end points from consideration. Also at issue is the determining what is considered an adverse effect, and this has been summarized with a few examples in Table 24.2. In sum, the MRL or RfD is based on the less serious effects and no serious effects. The following are example effects not used in obtaining a NOAEL: decrease in body weight less than 10%, enzyme induction with no pathologic changes, changes in organ weight with no pathologic changes, increased mortality over controls that is not significant (p > 0.05), and hyperplasia or hypertrophy with or with out changes in organ weights.
24.3.1Default Uncertainty and Modifying Factors
Most extrapolations from animal experimental data in the risk assessments require the utilization of uncertainty factors. This is because we are not certain how to extrapolate across species, with species for the most sensitive population, and across duration. To account for variations in the general population and to protect sensitive subpopulations, an uncertainty factor of 10 is used by EPA and ATSDR. The value of 10 is derived from a threefold factor for differences in toxicokinetics and for threefold factor for toxicodynamics. To extrapolate from animals to humans and account for interspecies variability between humans and other mammals, an uncertainty factor of 10 is used by EPA and ATSDR, and as with intraspecies extrapolations, this 10-fold factor is assumed to be associated with in toxicodynamics and toxicokinetics. An uncertainty
Table 24.2 Comparison of Less Serious Effects and Serious Effects
Less Serious |
Serious |
|
|
Reversible cellular changes |
Death |
Necrosis, metaplasia, or atrophy |
Cancer |
|
Clinically significant organ impairment |
Delayed ossifciation |
Visceral or skeletal abnormalities |
Alteration in offspring weight |
Cleft palate, fused ribs |
Altered T-cell activity |
Necrosis inn immunologic components |
Auditory disorders |
Visual disorders |
50% Reduction in offspring |
Abnormal sperm |
|
|
NONCANCER RISK ASSESSMENT |
429 |
factor of 10 is used when a NOAEL derived from a subchronic study instead of a chronic study is used as the basis for a calculation of a chronic RfD (EPA only). Note that ATSDR does not perform this extrapolation but derive chronic and subchronic MRLs. An uncertainty factor of 10 is used in deriving an RfD or MRL from a LOAEL when a NOAEL is not available. It should be noted that there are no reference doses for dermal exposure, however when there is insufficient dermal absorption data, the EPA uses a default factor of 10% to estimate bioavailability for dermal absorption. A modifying factor ranging from 1 to 10 is included by EPA only to reflect a qualitative professional assessment of additional uncertainties in the critical study and in the entire data base for the chemical not explicitly addressed by preceding uncertainty factors.
Refinements of the RfC have utilized mechanistic data to modify the interspecies uncertainty factor of 10 (Jarabek, 1995). The reader should appreciate that with the inhalation route of exposure, dosimetric adjustments are necessary and can affect the extrapolations of toxicity data of inhaled agents for human health risk assessment. The EPA has included dosimetry modeling in RfC calculations, and the resulting dosimetric adjustment factor (DAF) used in determining the RfC is dependent on physiochemical properties of the inhaled toxicant as well as type of dosimetry model ranging from rudimentary to optimal model structures. In essence, the use of the DAF can reduce the default uncertainty factor for interspecies extrapolation from 10 to 3.16.
The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3.
Much of the research efforts in risk assessment are therefore aimed at reducing the need to use these default uncertainty factors, although the risk assessor is limited by data quality of the chemical of interest. With sufficient data and the advent of sophisticated and validated physiologically based pharmacokinetic models and biologically based dose-response models (Conolly and Butterworth, 1995), these default values can be replaced with science-based factors. In some instances there may be sufficient data to be able to obtain distributions rather than point estimates.
24.3.2Derivation of Developmental Toxicant RfD
Developmental toxicity includes any detrimental effect produced by exposures during embryonic development, and the effect may be temporary or overt physical malformation. Adverse effects include death, structural abnormalities, altered growth, and
430 HUMAN HEALTH RISK ASSESSMENT
functional deficiencies. Maternal toxicity is also considered. The evidence is assessed and assigned a weight-of-evidence designation as follows: category A, category B, category C, and category D. The scheme takes into account the ratio of minimum maternotoxic dose to minimum teratogenic dose, the incidence of malformations and thus the shape of the dose-response curve or dose relatedness of the each malformation, and types of malformations at low doses. A range of uncertainty factors are also utilized according to designated category as follows: category A = 1–400, category B = 1–300, category C = 1–250, and category D = 1–100. Developmental RfDs are based a short duration of exposure and therefore cannot be applied to lifetime exposure.
24.3.3 Determination of RfD and RfC of Naphthalene with the NOAEL Approach
The inhalation RfC for naphthalene was 0.003 mg/m3, and this RfC was derived from a chronic (2-year) NTP inhalation study in mice using exposures of 0, 10, or 30 ppm (NTP, 1992). Groups of mice were exposed for 5 days a week and 6 hours a day. This study identified a LOAEL of 10 ppm. A dose-related incidence of chronic inflammation of the epithelium of the nasal passages and lungs was observed. This LOAEL concentration was normalized by adjusting for the 6-hour-per-day and 5-day-per-week exposure pattern. A LOAEL of 9.3 mg/m3 was obtained was derived by converting 10 ppm first to mg/m3 and then duration-adjusted levels for 6 h/day and 5 days/week for 103 weeks. An UF of 3000 was used, where 10 was for the interspecies (mice to humans) extrapolations, 10 for intraspecies variation in humans, 10 for using a LOAEL instead of a NOAEL, and 3 for database deficiencies.
The oral RfD for naphthalene was 0.02 mg/kg/day, and a study by Battelle (1980) was used to calculate the RfD. Decreased body weight was the most sensitive end point in groups of Fischer 344 rats given 0, 25, 50, 100, 200, or 400 mg/kg for 5 days/week for 13 weeks. These doses were also duration-adjusted to 0, 17.9, 35.7, 71.4, 142.9, and 285.7 mg/kg/day, respectively. The NOAEL for a > 10% decrease in body weight in this study was 71 mg/kg/day. The UF of 3000 was based on 10 for rats to humans extrapolation, 10 for human variation, 10 to extrapolate from subchronic to chronic, and 3 for database deficiencies including lack of chronic oral exposure studies.
24.3.4Benchmark Dose Approach
There are several problems associated with using the NOAEL approach to estimate RfDs and RfCs. The first obvious constraint is that the NOAEL must by definition be one of the experimental doses tested. Once this dose is identified, the rest of the dose-response curve is ignored. In some experimental designs where there is no identifiable NOAEL but LOAEL, the dose-response curve is again ignored, and the NOAEL is derived by application of uncertainty factors as described earlier. This NOAEL approach does not account for the variability in the estimate of the dose response, and furthermore experiments that test fewer animals result in larger NOAELs and thus larger RfDs and RfCs.
An alternative approach known as the benchmark dose (BMD) approach has been developed and implemented by risk assessors as an alternative to the NOAEL approach to estimate RfDs and RfCs. This approach is not constrained by experimental design
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